TY - JOUR
T1 - What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations
AU - Panagiotou, Orestis A.
AU - Ioannidis, John P.A.
AU - Hirschhorn, Joel N.
AU - Abecasis, Goncalo R.
AU - Frayling, Timothy M.
AU - McCarthy, Mark I.
AU - Lindgren, Cecilia M.
AU - Beaty, Terri H.
AU - Eriksson, Nicholas
AU - Polychronakos, Constantin
AU - Kathirensan, Sekar
AU - Plenge, Robert M.
AU - Spritz, Richard
AU - Payami, Haydeh
AU - Martin, Eden R.
AU - Vance, Jeffery
AU - Su, Wen Hui
AU - Chang, Yu-Sun
AU - Bei, Jin Xin
AU - Zeng, Yi Xin
AU - Paré, Guillaume
AU - Faraone, Stephen V.
AU - Neale, Benjamine
AU - Anney, Richard J.
AU - Traynor, Bryan J.
AU - Scherag, André
AU - Hebebrand, Johannes
AU - Hinney, Anke
AU - Froguel, Philippe
AU - Meyre, David
AU - Chanock, Stephen J.
AU - Kesheng, Wang
PY - 2012/2
Y1 - 2012/2
N2 - Background: Robust replication is a sine qua non for the rigorous documentation of proposed associations in the genome-wide association (GWA) setting. Currently, associations of common variants reaching P ≤ 5 × 10 -8 are considered replicated. However, there is some ambiguity about the most suitable threshold for claiming genome-wide significance.Methods We defined as 'borderline' associations those with P > 5 × 10 -8 and P ≤1 × 10 -7. The eligible associations were retrieved using the 'Catalog of Published Genome-Wide Association Studies'. For each association we assessed whether it reached P ≤ 5 × 10 -8 with inclusion of additional data from subsequent GWA studies.Results Thirty-four eligible genotype-phenotype associations were evaluated with data and clarifications contributed from diverse investigators. Replication data from subsequent GWA studies could be obtained for 26 of them. Of those, 19 associations (73%) reached P ≤ 5 × 10 -8 for the same or a related trait implicating either the exact same allele or one in very high linkage disequilibrium and 17 reached P < 10 -8. If the seven associations that did not reach P ≤ 5 × 10 -8 when additional data were considered are assumed to have been false-positives, the false-discovery rate for borderline associations is estimated to be 27% [95% confidence interval (CI) 12-48%]. For five associations, the current P-value is > 10 -6 [corresponding false-discovery rate 19% (95% CI 7-39%)].Conclusion A substantial proportion, but not all, of the associations with borderline genome-wide significance represent replicable, possibly genuine associations. Our empirical evaluation suggests a possible relaxation in the current GWS threshold. Published by Oxford University Press on behalf of the International Epidemiological Association
AB - Background: Robust replication is a sine qua non for the rigorous documentation of proposed associations in the genome-wide association (GWA) setting. Currently, associations of common variants reaching P ≤ 5 × 10 -8 are considered replicated. However, there is some ambiguity about the most suitable threshold for claiming genome-wide significance.Methods We defined as 'borderline' associations those with P > 5 × 10 -8 and P ≤1 × 10 -7. The eligible associations were retrieved using the 'Catalog of Published Genome-Wide Association Studies'. For each association we assessed whether it reached P ≤ 5 × 10 -8 with inclusion of additional data from subsequent GWA studies.Results Thirty-four eligible genotype-phenotype associations were evaluated with data and clarifications contributed from diverse investigators. Replication data from subsequent GWA studies could be obtained for 26 of them. Of those, 19 associations (73%) reached P ≤ 5 × 10 -8 for the same or a related trait implicating either the exact same allele or one in very high linkage disequilibrium and 17 reached P < 10 -8. If the seven associations that did not reach P ≤ 5 × 10 -8 when additional data were considered are assumed to have been false-positives, the false-discovery rate for borderline associations is estimated to be 27% [95% confidence interval (CI) 12-48%]. For five associations, the current P-value is > 10 -6 [corresponding false-discovery rate 19% (95% CI 7-39%)].Conclusion A substantial proportion, but not all, of the associations with borderline genome-wide significance represent replicable, possibly genuine associations. Our empirical evaluation suggests a possible relaxation in the current GWS threshold. Published by Oxford University Press on behalf of the International Epidemiological Association
KW - False-discovery rate
KW - Genome-wide association study
KW - Genome-wide significance
KW - Meta-analysis
KW - Replication
UR - https://www.scopus.com/pages/publications/84863338087
U2 - 10.1093/ije/dyr178
DO - 10.1093/ije/dyr178
M3 - 文章
C2 - 22253303
AN - SCOPUS:84863338087
SN - 0300-5771
VL - 41
SP - 273
EP - 286
JO - International Journal of Epidemiology
JF - International Journal of Epidemiology
IS - 1
M1 - dyr178
ER -